rs75568433

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_182914.3(SYNE2):c.14197C>A(p.Pro4733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,614,150 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4733R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 8 hom., cov: 32)

Exomes 𝑓: 0.015 ( 219 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.78

Publications

12 publications found

Variant links:

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SYNE2 links:

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ovarian dysgenesis 8
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ESR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005111128).

BP6

Variant 14-64130105-C-A is Benign according to our data. Variant chr14-64130105-C-A is described in ClinVar as [Benign]. Clinvar id is 313597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1552/152306) while in subpopulation NFE AF = 0.0172 (1168/68024). AF 95% confidence interval is 0.0164. There are 8 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1552 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.14197C>A	p.Pro4733Thr	missense_variant	Exon 76 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 link	c.14197C>A	p.Pro4733Thr	missense_variant	Exon 76 of 116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1555

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00975

AC:

2446

AN:

250990

AF XY:

0.00945

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00581

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00407

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0154

AC:

22445

AN:

1461844

Hom.:

219

Cov.:

AF XY:

0.0150

AC XY:

10907

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33480

American (AMR)

AF:

0.00624

AC:

279

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

428

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00211

AC:

182

AN:

86254

European-Finnish (FIN)

AF:

0.00446

AC:

238

AN:

53418

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0184

AC:

20423

AN:

1112004

Other (OTH)

AF:

0.0133

AC:

803

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1297

2594

3891

5188

6485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0102

AC:

1552

AN:

152306

Hom.:

Cov.:

AF XY:

0.00939

AC XY:

699

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41564

American (AMR)

AF:

0.00738

AC:

113

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00330

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1168

AN:

68024

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

168

251

335

419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0198

AC:

170

ExAC

AF:

0.00966

AC:

1173

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 15, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.029

.;T;T;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D;D;D

MetaRNN

Benign

0.0051

T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.1

M;.;M;.;.

PhyloP100

1.8

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.7

D;.;D;D;D

REVEL

Benign

0.15

Sift

Benign

0.11

T;.;T;T;T

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.61

MVP

0.51

MPC

0.34

ClinPred

0.022

GERP RS

5.8

Varity_R

0.14

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs75568433

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over